Dietary ellagic acid therapy for CNS autoimmunity: Targeting on Alloprevotella rava and propionate metabolism.

BACKGROUND: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. RESULTS: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. CONCLUSIONS: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract.

Targeting of KOR by famotidine promotes OPC maturation differentiation and CNS remyelination via STAT3 signaling pathway.

This study aims to identify FDA-approved drugs that can target the kappa-opioid receptor (KOR) for the treatment of demyelinating diseases. Demyelinating diseases are characterized by myelin sheath destruction or formation that results in severe neurological dysfunction. Remission of this disease is largely dependent on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLGs) in demyelinating lesions. KOR is an important regulatory protein and drug target for the treatment of demyelinating diseases. However, no drug targeting KOR has been developed due to the long clinical trials for drug discovery. Here, a structure-based virtual screening was applied to identify drugs targeting KOR among 1843 drugs of FDA-approved drug libraries, and famotidine was screen out by its high affinity cooperation with KOR as well as the clinical safety. We discovered that famotidine directly promoted OPC maturation and remyelination using the complementary in vitro and in vivo models. Administration of famotidine was not only effectively enhanced CNS myelinogenesis, but also promoted remyelination. Mechanically speaking, famotidine promoted myelinogenesis or remyelination through KOR/STAT3 signaling pathway. In general, our study provided evidence of new clinical applicability of famotidine for the treatment of demyelinating diseases for which there is currently no effective therapy.

Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target.

Neurodegenerative disorders (NDDs) are characterized by progressive loss of selectively vulnerable neuronal populations and myelin sheath, leading to behavioral and cognitive dysfunction that adversely affect the quality of life. Identifying novel therapies that attenuate the progression of NDDs would be of significance. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a widely expressed transcriptional regulator, modulates the expression of genes engaged in mitochondrial biosynthesis, metabolic regulation, and oxidative stress (OS). Emerging evidences point to the strong connection between PGC-1α and NDDs, suggesting its positive impaction on the progression of NDDs. Therefore, it is urgent to gain a deeper and broader understanding between PGC-1α and NDDs. To this end, this review presents a comprehensive overview of PGC-1α, including its basic characteristics, the post-translational modulations, as well as the interacting transcription factors. Secondly, the pathogenesis of PGC-1α in various NDDs, such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD) is briefly discussed. Additionally, this study summarizes the underlying mechanisms that PGC-1α is neuroprotective in NDDs via regulating neuroinflammation, OS, and mitochondrial dysfunction. Finally, we briefly outline the shortcomings of current NDDs drug therapy, and summarize the functions and potential applications of currently available PGC-1α modulators (activator or inhibitors). Generally, this review updates our insight of the important role of PGC-1α on the development of NDDs, and provides a promising therapeutic target/ drug for the treatment of NDDs.

"Rapid Formation, Acute Rupture" Course of Intracranial Aneurysm.

Intracranial aneurysm (IA) is a devastating cerebrovascular disease characterizing with a potential rupturing risk. In previous studies, the formation of IA was considered to be in a chronic manner, and the ruptured aneurysms might merely derived from the already formed unruptured IA. A 61-year-old male presented to the hospital complaining of a headache. The patient received neuroimage tests, including head computed tomography and digital substraction angiography, to examine the underlying cerebrovascular diseases. Interestingly, we found a newborn ruptured IA with 9-day intervals between 2 whole-cerebral digital subtraction angiography examinations. In summary, the case in our report provides a clue for the natural course that the IA is probably in a "rapid formation, acute rupture" manner.

2', 4'-Dihydroxy-2,3-dimethoxychalcone: A pharmacological inverse agonist of RORγt ameliorating Th17-driven inflammatory diseases by regulating Th17/Treg.

Multiple sclerosis, inflammatory bowel disease and organ transplant rejection are related to Th17 cell development and inflammatory respond. RORγt, a specific transcription factor regulating Th17 cell differentiation, is a pivotal target for the treatment of diseases. However, the clinical application of RORγt inverse agonists reported so far has been hindered due to limited efficacy and toxic side effects. Plant-derived natural products with drug-like properties and safety are wide and valuable resources for candidate drug discovery. Herein, structure-based virtual screening was used to find out 2',4'-Dihydroxy-2,3-dimethoxychalcone (DDC), a chalcone derivative rich in plants and food, located in the binding pocket of RORγt and targeted to inhibit RORγt activity. DDC repressed murine Th17 differentiation and promoted Treg differentiation remarkably in a dose-dependent manner. In addition, DDC treatment improved experimental autoimmune encephalomyelitis recovery, ameliorated experimental colitis severity, and prevented graft rejection significantly. Mechanically, DDC indirectly stabilized Foxp3 expression by inhibiting RORγt activity and the expression of its target gene profile in vitro and in vivo, which realized its regulation of Th17/Treg balance. In conclusion, our study provides a scientific basis that DDC, as an inverse agonist of RORγt with simple structure, rich sources, low cost, high efficiency, and low toxicity, has great potential for the development of a novel effective immunomodulator for the treatment of Th17-mediated inflammatory diseases.

[Screening of the Optimum Medium for Rat Mesenchymal Stem Cells].

OBJECTIVE: To investigate the effect of three different cell culture mediums, DMEM-LG, α-MEM and DMEM/F12, on the growth of rat bone marrow mesenchymal stem cells (BMSCs) in vitro, and so that to screen out the most suitable medium for in vitro culturing the rat BMSCs. METHODS: BMSCS were isolated from the femur and tibia of SD rats by whole bone marrow differential adherence method. The isolated cells were then cultured with three culture mediums, DMEM-LG, α-MEM and DMEM/F12. The rat BMSCs morphology, adhesion, proliferation, the time of passage and the number the colony at day 14 in three mediums respectively were observed with inverted phase contrast microscopy and compared. Flow cytometry was used to identify and observe the effects of different mediums on the surface antigen expression of rats BMSCs. RESULTS: Compared with the other two groups of media, BMSCs cultured in DMEM-LG had shorter colony formation time, shorter first passage time, more clone formation (14±2) and showed uniform morphology and the highest attachment efficiency (47.0±2.8)%. Meanwhile, BMSCs cultured with DMEM-LG entered logarithmic growth phase after only 4 days of culturing and showed the highest average specific growth rate and the largest average number of propagations per unit time. The total number of cells reached about (2.2-2.7)×105 mL-1 within three days. The cells cultured with 3 mediums were all identified as rat BMSCs, and the expression of surface antigen in BMSCs was not significantly affected by different media. CONCLUSION: DMEM-LG is more suitable for proliferation of rat BMSCs in vitro.